1. Field of the Invention
The present invention relates to an antitumor agent. More specifically, it relates to an antitumor agent containing, as effective ingredients, a pyrimidine type nucleic acid derivative and a 1-[(2-hydroxyethoxy)methyl]uracil derivative. In the antitumor agent of the present invention, the derivatives of 1-[(2-hydroxyethoxy)methyl]uracil are used in combination to inhibit decomposition of the pyrimidine type nucleic acid derivatives in living bodies when administered, whereby the utilization efficiency of 5-flouro-2'-de-oxyuridine in living bodies can be enhanced to exhibit an antitumor effect at a high level and a low dosage. The pyrimidine type nucleic acid derivative has an excellent antitumor activity in vitro, but a low effectiveness, for example, in oral administration.
2. Description of the Related Art
It has been reported that a pyrimidine type nucleic acid derivative including the acylated derivatives of 5-fluoro-2'-deoxyuridine has a higher by 10 to 100-fold antitumor activity in vitro as compared with a pyrimidine base derivative (see: Cancer Research, 35, 1121 (1975)).
Furthermore, it has been known in the art that 5-fluoro-2'-deoxyuridine is a compound having antitumor activity as one of the metabolites of 5-fluorouracil. Its antitumor activity has been reported to be 100-fold that of 5-fluoro-uracil at the same molar concentration, and 10 to 100-fold that of 5-fluorouridine, which is a metabolite of 5-fluorouracil, at the same concentration in inhibitory activity against the proliferation of an established cell line derived from a mouse in vitro (see: Cancer Res., 35, 1121 (1975); Cancer Res., 19, 494 (1959)).
However, in vivo tests using tumor-bearing animals, the effect of pyrimidine type nucleic acid derivatives is not sufficient, but contrary to the results in vitro, its antitumor effect has been reported to be inferior as compared with pyrimidine base derivatives such as 5-fluorouracil, and 5-fluorouridine (see: Cancer Res., 19, 494 (1959); Proc. Soc. Exp. Biol. Med., 97, 470 (1958); Proc. Soc. Exp. Biol. Mes., 104, 27 1960); Ann. N. Y. Acad. Sci., 76, 575 (1958).
Such results are considered to be attributable to the fact that pyrimidine type nucleic acid derivatives such as 5-fluoro-2'-deoxyuridine are rapidly decomposed by pyrimidine nucleoside phosphorylase such as uridine phosphorylase or thymidine phosphorylase in living bodies (see: Exp. Cell Res., Suppl. 9, 462 (1963); Biochem. Pharmac., 1, 328 (1959)), and further that 5-fluoro-2'-deoxyuridine has a shorter half-life in blood after administration in living bodies due to its physical and chemical properties to give an insufficient contact time with tumor cells (Cancer Res., 32, 1045 (1972); Clin. Pharmacol. Ther., 5, 581 (1964); Europ. J. Cancer, 16, 1087 (1980)).
For improving this drawback, studies have been heretofore made to chemically modify various pyrimidine type nucleic acids. For example, 3'-acyl-5-fluoro-2'-deoxyuridine (see: Japanese Unexamined Patent Publication (Kokai) No. 54-163586), 5-fluoro-2'-deoxyuridine acylated at the 3-position and at both the 3'- and 5'-positions (Japanese Unexamined Patent Publications (Kokai) Nos. 56-113795, 56-113796, 56-113797) are known. However, even in these derivatives, a satisfactory improvement is not obtained in potentiation of the antitumor effect.
Concerning 3',5'-diacyl-5-fluoro-2'-deoxyuridine, it is shown to have antitumor activity (Biochemical Pharmacology, 14, 1605 (1965)). Further, Japanese Unexamined Patent Publication (Kokai) No. 58-49315 discloses that said derivative has an antitumor activity at a lower dose as compared with 5-fluoro-2'-deoxyuridine.
However, since 3',5'-diacyl-5-fluoro-2'-deoxyuridine has a low water solubility, it can be applied for a preparation for injection of the prior art only with difficulty. On the other hand, when it is administered as an oral preparation, it has been reported to have a low antitumor effect, because it is mostly decomposed in the intestine in which esterase and uridine phosphorylase or thymidine phosphorylase activity is markedly greater as compared in other organs (Chem. Pharm. Bull., 33, 1652 (1985)).
On the other hand, 1-[(2-hydroxyethoxy) -methyl]uracils have been reported to become inhibitors against uridine phosphorylase in tumor cells and cytosol fractions of tumor cells and mouse liver (Biochem. Pharmac., 30, 2097 (1981); ibid, 31, 1857 (1982)). The effect of these compounds for pyrimidine nucleoside phosphorylase in normal digestive organs and the effect for pyrimidine nucleoside phosphorylase in normal liver homogenate have not been found at all. Further, there has been no reports of a simultaneous administration of a pyrimidine type nucleic acid derivative and a 1-[(2-hydroxyethoxy)methyl]uracil into the intestine by oral administration.
Accordingly, enhancement of the antitumor effect of 5-fluoro-2'-deoxyuridine by combined use of 1-[(2-hydroxyethoxy)methyl]uracils and 5-fluoro-2'-deoxyuridine may be considered. However, in this case, even when both may be administered at the same time, it is probable that the behavior of both in living bodies may differ, and therefore, it is not necessarily easy to obtain the effect of the combined use.